Methods and compositions for the treatment and diagnosis of diseases characterized by vascular leak, hypotension, or a procoagulant state

Abstract

Disclosed herein are methods for treating a vascular leak disorder, hypotension, or a procoagulant state using angiopoietin-2 (Ang-2) antagonist compounds. Also disclosed are methods for treating a vascular leak disorder associated with high dose IL-2 therapy using angiopoietin-2 antagonist compounds. Methods for diagnosing and monitoring vascular leak disorders, hypotension, or a procoagulant state that include the measurement of Ang-2 polypeptide or nucleic acid levels are also disclosed. Methods for inducing a vascular leak using an Ang-2 agonist are also disclosed.

1 . A method of treating vascular leak associated with high dose (HD) IL-2 therapy in a subject, said method comprising administering to said subject a compound that activates Tie-2 signaling, wherein said administering is for a time and in an amount sufficient to treat said vascular leak in said subject. 
     
     
         2 . The method of  claim 1 , wherein said compound blocks Ang-2 mediated inactivation of Tie-2. 
     
     
         3 . The method of  claim 2 , wherein said compound is an antibody. 
     
     
         4 . The method of  claim 3 , wherein said compound is L1-7(N). 
     
     
         5 . The method of  claim 4 , wherein said L1-7(N) is a chimeric, humanized, or fully human antibody. 
     
     
         6 . The method of  claim 1 , further comprising administering at least one compound selected from the group consisting of: an antibiotic, drotrecogin alpha, a corticosteroid, and vasopressin. 
     
     
         7 . The method of  claim 1 , further comprising administering to said subject a mechanical ventilation device. 
     
     
         8 . The method of  claim 1 , wherein said compound is administered intravenously or via bronchoscopic injection. 
     
     
         9 . The method of  claim 1 , wherein said compound is administered within 7 days of the start of the HD IL-2 therapy. 
     
     
         10 . The method of  claim 1 , wherein said compound is administered prior to the start of the HD IL-2 therapy to reduce the risk of developing vascular leak syndrome. 
     
     
         11 . The method of  claim 1 , wherein said method further comprises monitoring said vascular leak in said subject, wherein said monitoring comprises measuring the level of Ang-2 polypeptide in a sample from said subject. 
     
     
         12 . The method of  claim 11 , wherein said sample is serum or plasma and a level of Ang-2 polypeptide less than 10 ng/ml indicates an improvement in said vascular leak. 
     
     
         13 . The method of  claim 11 , wherein said measuring of levels is done on two or more occasions and a decrease in said levels between measurements is an indicator of an improvement in said vascular leak. 
     
     
         14 . The method of  claim 11 , wherein the level is compared to a positive reference sample and a decrease in the level of Ang-2 relative to said positive reference sample indicates an improvement in said vascular leak in said subject. 
     
     
         15 . The method of  claim 11 , wherein said monitoring is used to determine the therapeutic dosage of said compound that induces Tie-2 activity. 
     
     
         16 . The method of  claim 11 , wherein said measuring is done using an immunological assay. 
     
     
         17 . The method of  claim 11 , wherein said monitoring further comprises measuring the level of TNF-α, IL-1, IL-6, VEGF, or PlGF polypeptide in a sample from said subject. 
     
     
         18 . The method of  claim 1 , wherein said compound that activates Tie-2 signaling is an Ang-2 binding protein that blocks Ang-2 binding to Tie-2 receptor or a Tie-2 binding protein that specifically blocks Ang-2 binding to Tie-2 receptor. 
     
     
         19 . The method of  claim 18 , wherein said Tie-2 binding protein that specifically blocks Ang-2 binding to Tie-2 is an antibody.